Novel cyclopentanone-2-carboxylates

ABSTRACT

Novel alkyl 3-(3&#39;&#39;-OR-trans 1&#39;&#39;-alkenyl)-cyclopentanone-2carboxylates of the formula   WHEREIN Alk is alkyl of 1 to 7 carbon atoms, R is selected from the group consisting of hydrogen, acyl of an organic carboxylic acid of 1 to 18 carbon atoms and Alpha -tetrahydropyranyl and m is 3, 4 or 5 which are intermediates for prostaglandins and their preparation and novel intermediates.

Mite tates Martel et a tent 1 Feb. 25, 1975 NOVEL CYCLOPENTANONE-2-CARBOXYLATES [75] Inventors: Jacques Martel, Bondy; Edmond Toromanoff, Paris, both of France [73] Assignee: Roussel UCLAF, Paris, France [22] Filed: Nov. 15, 1972 {21] App], No.: 306,796

Related U.S. Application Data [62] Division of Ser. No. 138,274, April 28, 1971, Pat.

[52] U.S. CI 260/468 K, 260/468 D, 260/514 D [51] Int. Cl. C07c 69/74 [58] Field of Search 260/468 D, 468 K, 514 DK,

[56] References Cited OTHER PUBLICATIONS Martel et al., Tet. Letters, 1491 (1972). March, Advanced Organic Chemistry, p. 270-274 (1969).

Primary ExaminerR obert Gerstl Attorney, Agent, or Firm-I-Iammond & Littell [57] ABSTRACT Novel alkyl 3-( 3 '-OR-trans l -alkenyl)- cyclopentanone-2-carboxylates of the formula 4 Claims, N0 Drawings 1 NOVEL CYCLOPENTANONE-Z-CARBOXYLATES PRIOR APPLICATION This application is a division of our copending application Ser. No. 138,274, filed Apr. 28, 1971, now US.

Pat. No. 3,736,319.

wherein Alk is alkyl of l to 7 carbon atoms, R is selected from the group consisting of hydrogen, acyl of an organic carboxylic acid of l to 18 carbon atoms and a-tetrahydropy'ranyl and m is 3, 4 or 5. Particularly advantageous products are ethyl 3-(3'-oztetrahydropyranyloxy-trans l-octenyl) cyclopentanone-2-carboxylate and ethyl 3-(3'- hydroxy-tran s-l -octenyl)-cyclopentanon e-2- carboxylate.

The novel process for the preparation of the novel esters of formula I comprises reacting propargylacetic acid or a derivative thereof with a precursor agent for alkyl acetate to form alkyl 3-oxo-6-heptynoate of the formula HC 5 c -(cH2 2 C0 2 COOAlk wherein Alk is alkyl of l to 7 carbon atoms, reacting the latter with an etherification agent to form alkyl 3- alkoxy-6-yne -2-heptenoate of the formula ee-event:

wherein Alk is alkyl of l to 7 carbon atoms, condens-' ing the latter in the form of a metallic salt with anahalo-alkanal of the formula l '-alkenyl)-cyclopentanone-2- wherein I-Ial is bromine or chlorine and m is 3, 4 or 5 to form an alkyl '3-alkoxy-8-hydroxy-9-halo-6-yne-2- alkenoate of the formula Hell. 08

w. e I

-.":(ca -c=ca-'oomit lmhydrolyzing the latter with an acid agent to form alkyl 3-oxo-8-hydroxy-9 halo-6-alkynoate of the formula C @108 GH -NAIR hydrogenating the latter in the presence of a partially deactivated metallic catalyst to form alkyl 3-oxo-8- hydroxy-9-halo-cis 6-alkenoate of the formula p I on 5 l"; la

a CH-(FHQ-"X-CH -COOMK l I l I if v11 reacting the latter with an alkali metal alcoholate to form a trans epoxy-cis alkene of the formula ca moan:

reacting the latter with a secondary amine to form the corresponding enamine which is cyclized in the presence of a basic agent to form alkyl 3-(3-hydroxy-trans 1-alkenyl)-cyclopentanone-2-carboxylate of the formula and if desired reacting the latter with an acylating agent or an etherification agent to obtain the corresponding compound of formula I wherein R is a-tetrahydropyranyl or acyl of an organic carboxylic 'acid of 1 to 18 carbon atoms.

The cyclization in the presence of a basic agent is effected by intramolecular displacement SN of the ethylenic epoxy chain with an anion to confer stereospecific configuration of the natural products at the future 12 and 15 centers of prostaglandins. This reaction allows to resolve one 0f the principle difficulties in stereospecific synthesis of compounds of the type of formula I.

In the condensation of the alkyl 3-alkoxy-6-yne-2- heptenoate of formula III with a-halo alkanal of formula IV ,to form the compound of formula V, it is remarkable that the ethynyl group present is' compatible with the reaction conditions necessary to effect the condensation without secondary intramolecular or in termolecular reactions. It is very important to note that it is possible by this condensation to produce an ethylenic compound which ultimately leads by cis hydrogenation to the desired vinyl compound of formula Vll.

In a preferred embodiment of the process, propargyl acetyl imidazole (prepared by reacting propargyl acetic acid and N,N -thionyl-diimidazole) is treated with magnesium enolate of alkyl malonate such as ethyl malonate to form the alkyl 3-oxo-6-heptynoate of formula ll, etherifying the latter with an alkyl orthoformate in the presence of a strong acid such as sulfuric acid or ptoluene sulfonic acid to form the corresponding compound of formula III, reacting the latter in the form of a metallic salt such as lithium salt produced by reaction of an alkyl lithium such as butyl lithium in an ethertetrahydrofuran media with the a-halo alkanal in the same media to form a compound of formula V, subjecting the latter to hydrolysis with a mineral acid such as sulfuric acid or hydrochloric acid to form a compound of formula VI, hydrogenating the latter in the presence of palladium on a classic support such as barium sulfate, the catalyst being partially deactivated by the addition of lead acetate, of pyridine, of quinoline or a mixture of two of said compounds.

The epoxide is formed by treating a compound of formula Vll with an alkali metal alcoholate such assodium or potassium methylate, ethylate, tert.-amylate and tert.-butylate. The reaction is effected in an anhydrous media, preferably in the alcohol corresponding to alkali metal alcoholate used. The secondary amine to form the enamine of alkyl 3-oxo-trans 8,9-epoxy-cis alkenoate is selected from the group of cyclic amines such as pyrrolidine, piperidine and morpholine.

The basic agent for the cyclization may be an alkali metal amide such as sodium amide and the reaction is effected in an anhydrous organic solvent such as tetrahydrofuran.

The reaction ofa compound of formula I to form the corresponding a-tetrahydropyranyloxy compound is effected with dihydropyran in the presence ofa mineral or organic acid such as sulfuric acid or p-toluenesulfonic acid. To form the corresponding acyloxy derivative, the compound of formula I is reacted with an acylating derivative of the organic carboxylic acid of l to 18 carbon atoms such as the acid chloride or anhydride in the presence ofa basic agent such as pyridine, triethylamine or alkalimetal hydroxide.

Suitable organic acids of l to 18 carbon atoms may be derived from an aliphatic, aromatic, cycloaliphatic or heterocyclic carboxylic acid.

The compounds of formula I are useful intermediates for the preparation of compounds of the prostaglandin family which have known pharmaceutical properties. .The compounds can be reacted as described incopending, commonly assigned U.S. application Ser." No. 138,276 now U.S. Pat. No. 3,801,623 filed on even date herewith by reacting the a-tetrahydropyranyloxy compound of formula I in the presence ofa basic agent with an alkyl haloalkeneoate of the formula Hal-CH CH=CH (CH ),,-COOAlk wherein Hal is bromine or chlorine and Alk" is alkyl of l to 7 carbon atoms to obtain an alkyl carbalkoxyprostadieneoate of the formula treating the latter with an alkali metal alcoholate to obtain eem i lkz@29 2...

saponifying the latter with a basic agent to form a com- I pound of the formula which can be heated to form a prostadienic acid of the reacting the latter with an esterification agent derived formula from a lower alkanol, to form the corresponding ester GET C H M 2 8 F which is hydrolyzed in an acid media to'obtain a prosof the acid of formula XVII, hydrolyzing the said ester tanoic acid derivative of the formula in an acid mediate remove the q getrahydropyranyl e nv' The alkyl haloalkeneoates of formula IX may be pregroup and hydrogenating the resulting alkyl hydroxpared as described in copending, commonly assigned yalkyneoate in the presence of a partially deactivated US. Pat. application Ser. No. 138,275 filed on even catalyst to obtain a compound of the formula date herewith which comprises condensing a bromohaloalkane of the formula HO CH2 CH=CH (CH2)" COOAlkv reacting the latter with a halogenating agent to obtain Br (CH2)" Hal the corresponding alkyl haloalkeneoate of formula IX. XV The a-halo alkanals of formula IV may be prepared by a process analogous to that described by Krattiger wherein Hal is bromine or chlorine and n is 2, 3 or 4 [Bull. Soc. Chim., 1953, p. 222] which comprises rewith tetrahydropyranyl ether of propargyl alcohol in acting the desired halogen with the corresponding alkathe presence of an alkali metal in liquid ammonia to nal in an aqueous and strongly hydrohalic solution. form (tr-tetrahydropyranyloxy) haloalkyne of the for- In the following examples there are described several mula preferred embodiments to illustrate the invention. However, it should be understood that the invention is 4 0 not intended to be limited to the specific embodiments.

' l PREPARATION of Ethyl 3-(3'-oztetrahydropyranyloxy trans-l -octenyl)- reacting the latter with an alkali metal cyanide followed cyclopentanone-2-carboxylate by hydrolysis in a basic media to obtain (a-tetrahy- Step A: Ethyl 3-oxo-6-heptyneoate dropyranyloxy) alkynoic acid of the formula 7.3 g of ethyl malonate (Bram et a], Bull. S0c. Chim.,

1964, p. 945) were dissolved under a nitrogen atmosphere in 50 cc of tetrahydrofuran and then 0.10 mol of isopropyl magnesium bromide in solution in tetrahydrofuran was added. The mixture was heated slightly and allowed to return to room temperature while maintaining the nitrogen atmosphere to form solution A.

15 g of imidazole were dissolved in 100 cc of tetrahydrofuran and a solution of 6 g of thionyl chloride in 30 cc of tetrahydrofuran was added thereto. After stirring for 15 minutes, the mixture was filtered and the filter was washed with tetrahydrofuran to obtain a solution of N,N-thionyldimidazole, g of propargylacetic acid dissolved in 50 cc of tetrahydrofuran was added to the said solution and the mixture was stirred for 15 minutes at room temperature to obtain a solution of propargylacetylimidazole which was used as is.

Solution A was added to the solution of propargylacetylimidazole and the mixture was stirred overnight at room temperature. The mixture was acidified by addition of 4% hydrochloric acid and was extracted with ether. The ether phase was washed with an aqueous sodium bicarbonate solution, dried, treated with 'activated carbon, filtered and evaporated to dryness. The residue was passed through alumina with elution with methylene chloride to obtain 6.03 g of ethyl 3-oxo-6-heptynoate which was used as is for the next step.

The product occurred in the form of pale yellow prisms melting at 25C and soluble in alcohols, ether, benzene and chloroform and insoluble in water.

As far as is known, this compound is not described in the literature.

STEP B: Ethyl 3ethoxy-6-yne-2-heptenoate 30 cc of ethyl orthoformate and 0.35 cc of concentrated sulfuric acid were added to a solution of g of ethyl 3-oxo-6-heptynoate in 60 cc of ethanol and 25 cc of solvent were distilled off in 45 minutes while bubbling nitrogen therethrough. After cooling the mixture, methylene chloride was added thereto and the mixture was washed with 2N sodium hydroxide, The mixture was extracted with methylene chloride and the organic phases were dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with methylene chloride to obtain 7.05 g of ethyl 3-ethoxy-6-yne-2- heptenoate. The product occurred in the form of a pale yellow liquid soluble in alcohols, ether, benzene and chloroform and insoluble in water.

As far as is known, this compound is not described in the literature.

STEP C: Ethyl 3-ethoxy-8hydroxy-9-chloro-6-yne-2- tetradecenoate 9.25 cc of an ether solution of 1.085 N butyllithium were added to a mixture of 2 g of ethyl 3-ethoxy-6-yne- 2-heptenoate and cc of tetrahydrofuran cooled to -25C and the mixture was left standing at 25C for l- /2 hours. After cooling the mixture to 30C, 3 g of a-chloroheptanal (process of Krattiger, Bull. Soc. Chim., 1953, p. 222) were added thereto and the mixture stood for 30 minutes at C, at 0C for 30 minutes and then returned to room temperature. The reaction mixture was added to an iced aqueous solution of monosodium phosphate and was extracted with ether. The organic phase was washed with aqueous sodium bicarbonate solution, then water and finally with aqueous sodium chloride solution. The solution was dried low product soluble in alcohols and ether and insoluble in water.

Analysis: C,,,H ,,O ,Cl; molecular weight 344.87 Calculated: Cl 10.28 Found: 10.3 U. V. Spectrum (ethanol):

Max. at 237 mu E, 357

As far as is known, this product is not described in the literature. STEP D: tetradecynoate A mixture of 6.95 g of ethyl 3-ethoxy-8-hydroxy-9- chloro-6yne-2-tetradecynoate, 70 cc of ethanol and 35 cc of 2N hydrochloric acid was heated with stirring under a nitrogen atmosphere at C forl r hours, and after cooling, water was added to the reaction mixture which was extracted with methylene chloride. The organic phase was washed with an aqueous sodium bicarbonate solution and then water until the wash waters were neutral, dried over sodium sulfate filtered and evaporated to dryness under reduced pressure to obtain 6 g of raw ethyl 3oxo-8-hydroxy-9-chloro-6- tetradecynoate. The product was purified by chromatography over silica gel and elution with a 70-30 mixture of cyclohexane-ethyl acetate to obtain pale yellow crystals soluble in alcohols and ether and insoluble in water.

Ethyl 3oxo-8hydroxy-9-chloro-6- As far as is known, this product is not described in the literature.

STEP E: Ethyl 3-oxo-8hydroxy-9-chloro-cis-6- tetradeccnoate 240 mg of 5% palladium on barium sulfate were added to 15 cc of ethylacetatc and a current of hydrogen was passed therethrough for 30 minutes. After absorption of 6 cc of hydrogen, a solution of 3.03 g of ethyl 3oxo-8-hydroxy-9-chloro-6-tetradecynoate in 5 cc of ethyl acetate containing 0.3 cc of quinoline was added thereto and was washed with 10 cc of ethyl acetate. The current of hydrogen was passed through the mixture for 2 hours and after absorption of 223 cc of hydrogen, the mixture was filtered. The filter was washed with ethyl acetate and the organic phase was washed with 0.5N hydrochloric acid, then with water and was dried over sodium sulfate, treated with activated carbon and filtered. The filtrate was evaporated Analysis: C H O Cl; molecular weight 318.84

Calculated: H 8.54 Cl 11.12 Found: 60.0 8.4 10.8 U.V. Spectrum (ethanol):

Max at 243 my. E 32 As far as is known, this compound is not described in the literature. STEP F: tetradecenoate 32 cc of a solution of 1N potassium tertiary butylate in tertiary butanol were added under nitrogen to a solution of g of ethyl 3-oxo-8-hydroxy-9-chloro-cis-6- tetracecenoate in 50 cc of tertiary butanol and the mixture was stirred for 45 minutes. Methylene chloride was added thereto and the mixture was poured into a saturated aqueous solution of monosodium phosphate. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel with elution with a 1:1 mixture of cyclohexane and ethyl acetate to obtain 3.4 g of ethyl 3-oxo-trans 8, 9-epoxy-cis -tetradecenoate in the form of a pale yellow liquid, soluble in most of the usual organic solvents and insoluble in water.

Ethyl 3-oxo-trans-8,9-epoxy-cis-6- Analysis: G -H 0 molecular weight 282.38 Calculated: C 68.05 H 9.28 Found: 68.3 9.4

U. V. spectrum (ethanol):

Max. at 246 mu E 49 As far as is known, this compound is not described in the literature. STEP G: Ethyl 3-N-pyrrolidyl-trans 8,9-epoxy-2-cis 6 tetradecadienoate A mixture of 1.5 g of ethyl 3-oxo-trans 8,9-epoxy-cis 6-tetradecenoate, cc of benzene, 1.5 cc of pyrrolidine and 75 mg of p-toluene sulfonic acid was purged with nitrogen and was then stirred at room temperature for 4 days. At the end of this time, the mixture was evaporated to dryness under reduced pressure and toluene was added to eliminate excess pyrrolidine. The residue was dissolved in methylene chloride and the organic phase was washed with water. The wash waters were re-extracted with methylene chloride and the combined methylene chloride phases were dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 1.9 g of ethyl 3-N-pyrrolidyl-trans 8,9- epoxy-2-cis o-tetradecadienoate in the form of dark yellow amorphous solid soluble in alcohols and chloroform and insoluble in water.

U.V. Spectrum (ethanol): lnflex. towards 230 mu E. m 7 Max. at 289-290 mp.

lR Spectrum:

Absence of OH and bands at 1671, 1565, 1446 and 1143 cm- Y As far as is known, this compound is not described in the literature. Step H: Ethyl 3-(3"-hydroxy-trans cyclopentanone2-carboxylate 4.3 g of sodium amide were added under nitrogen to 9.3 g of ethyl 3-N-pyrrolidyl-trans 8,9-epoxy-2 cis 6- tetradecadienoate in l 10 cc of tetrahydrofuran and the mixture was stirred overnight at room temperature. The mixture was poured into an iced aqueous solution of monosodium phosphate and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under. reduced pressure. The residue was chromatographed over silica gel to obtain 3.4 g of ethyl 3-( 3 -hydroxy-trans 1-octenyl)-cyclopentanone-2- carboxylate in the form of a yellowliquid soluble in alcohols, ether, benzene and chloroform and insoluble in water.

l-octenyl)- Analysis: C H O N molecular weight 476.47

(dinitrobenzoate) Calculated: C 57.98 H 5.88 '70 N 5.88

Found: 57.8 6.0 6.1

As far as is known, the compound is not described in the literature. Step 1: Ethyl 3-(3-a-tetrahydropyranyloxy-trans loctenyl)-cyclopentanone-2-carboxylate 4 crystals of p-toluene sulfonic acid and then 4 cc of dihydropyran were added to a solution of 3g of ethyl 3-(3-hydroxytrans l'-octenyl) cyclopentanone-2- carboxylate in 10 cc of ether cooled to 0C and the mixture was allowed to return to room temperature. The mixture was added to anhydrous sodium carbonate and was stirred for 1 hour under nitrogen. After filtration, the solvent and excess dihydropyran was evaporated off under reduced pressure to obtain 3.89 g of ethyl 3-(3-a.tetrahydropyranyloxy-trans l'-octenyl)- cyclopentanone-2-carboxylate in the form of a colorless liquid soluble in alcohols, ether and chloroform and insoluble in water.

Analysis: C H O molecular weight 366 Calculated: C 68.85 70 H 9.29 Found: 68.9 9.0

As far as is known, this compound is not described in the literature.

EXAMPLE ll Ethyl 3-ethoxy-6-yne-2-heptenoate A mixture of 10.1 g of ethyl 3-oxo-6-heptyn oate, 100 cc of ethanol, 20 cc of ethyl ortho formate and 1 g of p-toluene sulfonic acid was refluxed under nitrogen for minutes and after cooling, methylene chloride was added to the mixture which was then poured into cc of iced N sodium hydroxide. The organic phases were washed with iced N sodium hydroxide and then with an aqueous sodium chloride solution and reextracted the wash solutions with methylene chloride.

The combined organic phases were dried over sodium A mixture of the said deposit in 22 cc of ethanol and sulfate, filtered and evaporated to dryness under re- 1 13 cc ofa saturated cupric acetate solution was stirred duced pressure. The residue was subjected to chromaovernight and then decanted. The cupric complex tography over silica gel and elution with methylene formed was washed with water and vacuum filtered. chloride to obtain 6.716 g of ethyl 3-ethoxy-6-yne -2- 5 The complex was suspended in petroleum ether and heptenoate identical to that obtained in Step B of EX- was stirred for l hour in an ice-water bath. The mixture ample l. was filtered and the filter was washed with iced petroleum ether and then an iced 2-l mixture of petroleum EXAMPLE I" ether and ether. The precipitate was dissolved in methm ylene chloride and the solution was acidified with dilute Ethyl acetic acid and added to methylene chloride. The A mixture of g of ethyl 3'ethoxy6yne'2'hepten methylene chloride phase was washed with water, then Date and 110 CC of tetrahydmfuran was Cooled to aqueous sodium bicarbonate solution and then with and 29 cc of a Solution of N butyni' water until the wash waters were neutral. The solution thium in hexane was added and then stirred for 3 hours. was dried Over magnesium lf t d evaporated to A SOiUtiOI'l Of g Of a-chloro-heptanal in CC Of tetdryness to btain ethyl 3 0 o-8-hydroxy.9-ehloro-6- rahydrofuran was added thereto and the mixture was tetradecynoate identical to that of Step D of Example stirred for one hour at 60C and then was allowed to return to room temperature. The reaction mixture was v i difi i f h process d d t f added to an iced saturated aqueous solution of monoh invention may b d i h departing f h sodium phosphate and the m Xture W eXtraCted With spirit or scope thereof and it is to be understood that ether. The ether phase aS Washed ith n queo the invention is to be limited only as defined in the aplution saturated of sodium bicarbonate, then with water d d cl i until the wash waters were neutral, dried over sodium We claim: sulfate and evaporated to dryness. 1. A 3-(3-OR-trans 1'-alkenyl)cyclopentanone2- The residue was dissolved in l0 0 cc of ethanol and carboxylate of the formula i c AlkOOC !H l c i (c11 CH H I 6R 56.5 cc of 2 N hydrochloric acid and the mixture was wherein Alk is alkyl of l to 7 carbon atoms. R is hydrostirred under a nitrogen atmosphere at to 60C for gen and m is 3. 4 or 5.

1- /2 hours. After cooling, the solution was added to a 2. The compound of claim 1 wherein Alk is ethyl. water-ice mixture and was extracted with ether. The 3. A process for the preparation of an alkyl 3-(3'- ether phase was washed with water until the wash wahydroxy-trans l-alkenyl)-cyclopentanone-2- ters were neutral, dried over magnesium sulfate and 40 Ca O Y ate 0f the formula evaporated to dryness to obtain 16 g of ethyl 3-ox0-8- wherein Alk is alkyl of l to 7'carbon atoms and m is 3, hydroxy-9-chloro-6-tetradecynoate. 4 or 5 comprising cyclizing with an alkali metalamide the enamine of the trans epoxy-cis alkene of the for- Volatile products contained in the 16 g of raw prodmula uct were removed by distillation under reduced presk sure and at the end of the distillation, the residue was ca 08-03-084 3 n 2 cooled and was taken up in ether. The solution was 8 treated with activated carbon. filtered and evaporated to dryness. The residue was dissolved in 5 cc ot'lsopro- 2 pyl ether and was added to 4 volumes of petroleum 0 wherein Alk is alkyl of l to 7 carbon atoms and m is 3.

ether with agitation. The solution was cooled to C 4 or 5. and petroleum ether was added until there was forma- 4. The process of claim 3 wherein the enamine is detion of a deposit and was decanted. rived from a cyclic amine. 

1. A 3-(3''-OR-TRANS 1''-ALKENYL)CYCLOPENTANONE2CARBOXYLATE OF THE FORMULA
 2. The compound of claim 1 wherein Alk is ethyl.
 3. A process for the preparation of an alkyl 3-(3''-hydroxy-trans 1''-alkenyl)-cyclopentanone-2-carboxylate of the formula
 4. The process of claim 3 wherein the enamine is derived from a cyclic amine. 